What is the role of blood-brain-barrier regional specificity in the nucleus accumbens?

项目摘要/摘要 血脑屏障(Bbb)是一个描述中枢神经系统(Cns)独特特性的术语。 血管，使它们能够严格调节周围神经的细胞外环境 组织。虽然众所周知，不同的大脑区域由不同的细胞类型组成，并执行不同的 功能，目前还不清楚血脑屏障是否在不同的功能区域表现出不同的特征，以调节特定的 神经回路。由于人们对血脑屏障的异质性知之甚少，这个项目将在 认识和追寻血脑屏障的地区性专业化是否可以调节 本地电路功能和行为。这将识别血脑屏障是否可以被作为调节特定行为的目标， 包括奖励和上瘾。 单细胞RNA测序显示，血脑屏障具有显著的区域间异质性 血管内皮细胞的差异基因表达。而对人类健康有贡献的典型的BBB基因 限制性屏障特性在所有脑区的内皮细胞中都有表达，许多参与运输的基因， 信号和代谢被发现在特定脑区的内皮细胞中丰富。例如，Stra6，a 维甲酸转运调节剂，在伏隔核外壳(SNAC)和腹侧显著丰富 耳蜗核(VCN)与大脑的其他区域相比。SNAC特别令人感兴趣，因为它 奖赏和强化学习的功能与药物成瘾的区域有关。由于流行率和 鉴于成瘾的严重性，迫切需要找到新的目标，通过以下方式解决这一重大公共卫生问题 通过Stra6询问血脑屏障是否在调节成瘾方面发挥作用。 拟议的研究将通过确定(1)Stra6在 血脑屏障对于SNAC的发育或成人功能是必需的，(2)通过什么分子机制Stra6 调节SNAC功能，以及(3)学习成瘾行为是否需要Stra6。这项提案将考验 假设Stra6在SNAC内集中维甲酸，从而动态调节多巴胺受体 因此，SNAC在空间学习和成瘾方面的成人功能。Stra6在美国的重要性 BBB将使用有条件的EC特异性Stra6基因敲除小鼠在发育过程中切除Stra6进行测试 或者在成年后。这些目标还将测试提高饮食中的维生素A--维甲酸的来源--是否可以 在没有Stra6的情况下增加维甲酸水平，挽救SNAC功能。这项提议的中心目标是 为了更深入地了解血脑屏障对大脑功能的贡献，详细说明成瘾的机制，以及 评估哪些因素可能会增加个体对药物成瘾的易感性。

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is a term that describes the unique properties of central nervous system (CNS) blood vessels which allow them to stringently regulate the extracellular environment of the surrounding neural tissue. While it is known that different brain regions are made up of diverse cell types and execute distinct functions, it is unknown if the BBB exhibits varied features in functionally distinct regions to regulate specific neural circuits. Since little is known about heterogeneity of the BBB, this project will address this gap in knowledge and pursue the question of whether regional specializations of the blood-brain barrier may regulate local circuit function and behavior. This will identify if the BBB could be targeted to modulate specific behaviors, including reward and addiction. Single cell RNA sequencing revealed that there is significant inter-regional heterogeneity of the BBB via differential gene expression in endothelial cells (ECs). While the canonical BBB genes that contribute to restrictive barrier properties were expressed in ECs across all brain regions, many genes involved in transport, signaling, and metabolism were found to be enriched in ECs of specific brain regions. For instance, Stra6, a transport regulator of retinoids, is remarkably enriched in the nucleus accumbens shell (sNAc) and the ventral cochlear nucleus (VCN) compared to other areas of the brain. The sNAc is particularly of interest because its function in reward and reinforcement learning implicates the region in drug addiction. Due to the prevalence and severity of addiction, it is urgently important to find new targets for treating this major public health issue by asking if the BBB, via Stra6, plays a role in regulating addiction. The proposed study will address this critical need by determining (1) if the regional specificity of Stra6 at the BBB is necessary for the development or adult function of the sNAc, (2) by what molecular mechanisms Stra6 regulates sNAc function, and (3) if Stra6 is required for learning addiction behavior. This proposal will test the hypothesis that Stra6 concentrates retinoids within the sNAc, thereby dynamically regulating dopamine receptor levels and thus the adult function of the sNAc in both spatial learning and addiction. The importance of Stra6 at the BBB will be tested using conditional, EC-specific Stra6 knockout mice to excise Stra6 during development or in adulthood. These aims will also test whether elevating dietary Vitamin A, the source of retinoids, can increase retinoid levels in the absence of Stra6 and rescue sNAc function. The central goals of this proposal are to gain deeper understanding of the BBB’s contribution to brain function, specify mechanisms of addiction, and assess what factors might increase individual susceptibility to drug addiction.